Method for purifying phthalides

ABSTRACT

Phthalides in as-obtained phthalide synthesis reaction mixtures are recovered in pure form by(a) distilling compounds having a boiling point below the boiling point of the phthalide from the reaction mixture, provided such compounds are present in the reaction mixture, to obtain a crude phthalide as bottom product,(b) crystallizing the phthalide from a melt of the crude phthalide.

The present invention relates to a process for recovering phthalidesfrom as-obtained phthalide synthesis reaction mixtures.

Phthalides, i.e., substituted lactones of 2-(hydroxymethyl)benzoic acid,and phthalide itself (isobenzofuran-1(3H)-one) are required especiallyas intermediates for the synthesis of crop protection agents or drugs.

Various processes for preparing phthalides are known. Phthalides arepredominantly prepared by means of electrochemical processes, byhomogeneously or heterogeneously catalyzed hydrogenation.

DE-A 21 44 419 describes a process for the electrochemical preparationof phthalide. An aqueous solution of ammonium phthalamate is cathodically reduced at electrolysis temperatures of up to 65° C. over metalshaving a hydrogen overpotential greater than that of copper. High puritylead in particular is used as cathode material. To work up, any excessammonia and solvent and some of the water are distilled off. A solutionof the primary reaction product, the ammonium salt ofo-aminomethylbenzoic acid, is left behind and is treated with a strongacid to precipitate phthalide. The phthalide is isolated by filtration.Product still in solution can be extracted with benzene. The productobtained can be further purified by recrystallization from hot water.

DE-A 25 10 920 describes a process for electrochemical preparation ofphthalide. An ammoniacal aqueous solution of phthalic anhydride or acidis cathodically reduced at up to 100° C. over metals having a hydrogenoverpotential greater than that of copper. The reaction mixture isworked up by distilling any excess ammonia and/or water out of theelectrolysis mixture to separate off the phthalide and acidifying theresidue at from 35 to 100° C.

Prior DE-A 196 18 854, unpublished at the priority date of the presentinvention, describes a process for preparing phthalides by cathodicreduction of phthalic acid derivatives. Reduction is carried out in anorganic solvent comprising less than 50% by weight of water in anundivided electrolysis cell. It is stated that the workup can beeffected by distillation, precipitation or recrystallization. Inaddition, the phthalides can be dissolved in ammoniacal aqueoussolutions, then the aqueous phase separated off and the phthalidereprecipitated by acidification of the aqueous phase. The exemplifiedworkup involves distillative removal of the solvent mixture and vacuumdistillation of the phthalide.

The distillation has to be carried out at a high temperature level inthe region of the boiling point of the phthalides, so that the productis subjected to considerable thermal stress for a prolonged period. Inaddition, distillation is not in all cases suitable for obtaining a purephthalide. Specifically in the case of the electrochemical preparationof phthalides starting from methyl phthalates, unconverted methylphthalates and phthalide form an azeotrope which cannot be separated bydistillation. If the proportion of methyl phthalate remaining in theproduct is to be minimized by the way the reaction is conducted, thephthalide yield decreases and other, secondary products can appear.

Recrystallizing the phthalides involves dissolving them in a solvent andcooling the solution to crystallize them out again. It is thus necessaryto provide a solvent and to separate it again from the pure phthalide atsome inconvenience. Handling the solvent in a closed-loop systemrequires complex processing technology. After the crystallizate has beenseparated from the mother liquor, the mother liquor has to beconcentrated in order that it may be further processed. The productobtained may include residual solvent, which has to be removed bydrying.

It is an object of the present invention to provide a process forrecovering phthalides from as-obtained phthalide synthesis reactionmixtures without the disadvantages of existing workups. Moreparticularly, the process shall not require the use of solvents or ofother assistants, shall keep the thermal stress on the phthalides to aminimum and shall be economical to carry out in energy terms.

We have found that this object is achieved according to the invention bya process for recovering phthalide from an as-obtained phthalidesynthesis reaction mixture by

(a) distilling compounds having a boiling point below the boiling pointof the phthalide from the reaction mixture, provided such compounds arepresent in the reaction mixture, to obtain a crude phthalide as bottomproduct,

(b) crystallizing the phthalide from a melt of the crude phthalide.

The phthalide is crystallized from a melt of the crude phthalide, i.e.,without use of other solvents or other assistants, as required, forexample, for a recrystallization.

The solvent-free crude phthalide is in turn obtained from the reactionmixture by distillative removal of compounds having a lower boilingpoint than the desired phthalides. If such compounds are present in thereaction mixtures, they are thus removed by distillation prior to thecrystallization. The bottom product of the distillation is a crudephthalide, and the thermal stress involved in removing the low boilingcompounds is considerably less than the thermal stress that would beinvolved in an additional, subsequent distillation of the phthalide. Thecrude phthalide used for the crystallization is thus substantially or,preferably, completely free from solvents or lower boiling compounds.

In one embodiment of the invention, the crystallizing is effected on acooled surface on which the crystals grow.

So the liquid crude phthalide is brought into contact with a coolingsurface, and phthalide crystals are formed thereon. On completion of thecrystallization phase, the remaining liquid (mother liquor) is removed.The purity of the phthalide crystals remaining on the cooling surfacecan be increased by partially melting off (sweating) comparativelyimpurer portions of the crystals. In addition, the purity of thecrystals on the cooling surface can be increased by washing, for examplewith the crude phthalide feed or with liquid phthalide of higher purity.Finally, the purified crystals are liquefied by heating, and theresulting melt of the pure phthalide is removed from the coolingsurface.

The cooling surface where the crystallization is carried out is notsubject to any restriction; it may have any desired suitable shape. Thetemperature of the melt during the crystallization is preferably withinthe range from −10 to 75° C., particularly preferably within the rangefrom 20 to 70° C. The solids content in the crystallizer is customarilywithin the range from 10 to 90 g, preferably within the range from 30 to80 g, per 100 g of crude phthalide feed.

The crystallization can be carried out continuously or batchwise, in onestage or in a plurality of stages.

The crystallization on the cooled surface can be carried out as a staticcrystallization or as a dynamic layer crystallization. In the firstcase, the crude phthalide melt used is stationary. Such a staticcrystallization process is available for example from BEFS/Prokem(France) or from Sulzer Chemtech (Switzerland). In a dynamic layercrystallization, the melt of the crude phthalide is subjected to forcedconvection. Such a process is available for example from Sulzer Chemtech(Switzerland). In both process variants, the cooled surfaces aredisposed inside the crystallization apparatus, so that the crystalswhich form are immobilized inside the apparatus. Preference is given tothe use of a static crystallization, where the melt of the crudephthalide is stationary and only natural convection occurs.

The advantage of this process is that the product is subjected to only avery low thermal stress and that the temperature level required is low,keeping the energy requirement relatively low. The separation ofcrystals from the mother liquor can be effected without additionalequipment requirements.

The crystallization on a cooled surface is preferably effected inmultiple stages as a fractional crystallization. Fractionalcrystallization can also be employed in the case of the other suitablecrystallization processes, for example suspension crystallization.

Fractional crystallization makes it possible to raise the purity of thephthalides if one purification stage is not enough to achieve thedesired end-purity. Repeated crystallization of the respectivelyproduced pure fractions, which are then liquefied, can be used toachieve the desired end-purity.

In a fractional crystallization, all stages producing crystals of apurity higher than that of the crude phthalide feed are customarilyreferred to as purification stages, while all other stages are known asstripping stages. Multi-stage processes are advantageously operatedaccording to the countercurrent principle, whereby, in each stage, thecrystallizate is separated from the mother liquor after thecrystallization, and this crystallizate is fed into whichever is thestage having the next highest degree of purity, while thecrystallization residue is fed into the particular stage having the nextlowest degree of purity.

The fractional crystallization is preferably carried out with from 2 to10 stages, particularly preferably with from 2 to 4 stages, especiallywith 3 stages.

In a suspension crystallization, the melt of the crude phthalide iscrystallized by heat removal. The crystals which form are in suspensionin the remaining liquid phase (mother liquor). On attainment of adesired crystal content, customarily within the range from 10 to 40% byweight, the crystals are separated from the mother liquor. Afterseparation, the crystals can be liquefied and crystallized in a furtherstage.

Heat removal can be effected by cooling in a heat transferor, preferablya tube bundle heat transferor, through which the suspension passes,preferably on the tube side. If encrustation of the cooling surface islikely, a plurality of heat transferors, preferably 3 heat transferors,can be connected in parallel. One of the heat transferors is alwaystaken out of service, and the adhering phthalide crystals can be meltedoff by heating. This permits continuous operation. For example, thethermal conductivity of the heat transferor can be measured inoperation. When the thermal conductivity has become excessively low dueto crystal layer formation, operation is switched to a second heattransferor and so on. As well as melting off the adhering crystals, theycan also be removed by purging the heat transferor with a feed solutionof the phthalide. This also enables the feed to be precooled at the sametime.

The residence time required for crystal growth is made available in acrystallizer, preferably a forced circulation crystallizer, whosesuspension circuit accommodates the heat transferors.

In addition, heat removal from the suspension can be obtained by meansof a heat transferor having scraped cooling surfaces. Heat is removedvia scrape coolers connected to a stirred tank or to a vessel without astirrer. Circulation of the crystal suspension is insured in this caseby means of a pump. Alternatively, it is often possible to remove theheat via the walls of a stirred tank having a close-clearance stirrer. Afurther possibility is to combine heat removal and residence timecontrol in one piece of equipment. This is the case for example with acooling disk crystallizer as available for example from GoudscheMachinefabrik B.V. (Netherlands). The heat is removed via cooled plateswhich are wiped on both sides to avoid encrustations. The cooling platesare disposed in a cuboid shaped vessel in such a way that they divide itinto equidimensional segments, each of which is bounded by a coolingsurface on both sides. The suspension moves from segment to segment andhas a very narrow residence time spectrum. The cooling medium flowingwithin the cooling plates flows in the direction opposite to the flowdirection of the suspension. As a result, the suspension passing throughthe equipment undergoes a virtually continuous temperature lowering andcorrespondingly has an increasing crystal content.

The mother liquor and the crystallized phthalide can be suitablyseparated using any known solid-liquid separation process. For example,the crystals can be separated from the suspension via a centrifuge,especially a pusher centrifuge, or a filter, particularly preferably abelt filter or a turntable filter. Filtration or centrifugation can bepreceded by a prethickening of the suspension, for example by means ofhydrocyclones. As well as single- or multi-stage pusher centrifuges, itis also possible to use screw centrifuges or screw discharge centrifuges(decanters). Filtration can be effected batchwise or continuously, undersuperatmospheric pressure or at reduced pressure. If suction filters areused, they can be equipped with a stirrer.

Solid-liquid separation may be accompanied and/or followed by furtherprocess steps for increasing the purity of the crystals or of thecrystal cake. The crystals obtained in stage (b) can be further purifiedfor example by washing and/or sweating. In washing, the quantity of washliquor is preferably within the range from 10 to 500 g of washliquor/100 g of crystallizate, particularly preferably within the rangefrom 30 to 200 g of wash liquor/100 g of crystallizate. Suitable washliquors are for example the liquid pure product which is obtained bymelting the crystals obtained, or the liquid crude phthalide. Thewashing medium should have a higher purity than the mother liquor fromwhich the crystallizate was removed. Washing or sweating may in certaincircumstances save a further purification or crystallization step.

Washing can be effected in a customary washing apparatus. It isadvantageous to use wash columns in which the removal of the motherliquor and the washing take place in one and the same apparatus,centrifuges, which can be operated in one or more stages, or suctionfilters or belt filters. The washing can be carried out on centrifugesor belt filters in one or more stages. The wash liquor can be passed incountercurrent to the crystal cake.

Sweating describes a local melting-off of impure regions of thecrystals. The sweat quantity is advantageously within the range from 5to 35 g of molten-off crystallizate/100 g of crystallizate prior tosweating. It is particularly preferable to carry out the sweating onbelt filters. A combined wash and sweat in one apparatus can also besuitable.

A further way to increase the purity is to slurry up the removedcrystallizate and to subject the slurry to another separation. Theslurry can be formed in pure product or in the melt of the crudephthalide.

The purity of the phthalide obtained is preferably within the range from97 to 99.9% by weight, especially within the range from 98.5 to 99.5% byweight.

The step (b) crystallization of the phthalide from the melt of the crudephthalide is particularly preferably effected by three-stage static meltcrystallization.

The reaction mixture from which the phthalides are isolated canoriginate in any desired manufacturing process for the synthesis ofpthalides. For example, it can be produced in an electrolytic reductionas described for example in DE-A 21 44 419 and DE-A 25 10 920 or DE-A196 18 854. The reaction mixture may here comprise solvents, conductingsalts, anodic depolarizers, mediators or mixtures thereof.

In the electrolytic reduction process, especially phthalic acid orphthalic acid derivatives in which the carboxyl groups may be replacedby units derived from carboxyl groups in a condensation reaction, andone or more of the hydrogens of the o-phenylene unit of phthalic acidmay be substituted by inert radicals, are dissolved in an electrolyteand reduced at a cathode in an undivided electrolysis cell.

The starting compounds used for preparing the phthalides are inparticular those of the general formula (I)

where the substituents have the following meanings:

R¹, R², R³ and R⁴: are each, independently of one another, hydrogen,C₁-C₄-alkyl or halogen,

R⁵, R⁶:

(a) are each, independently of each other, —COOH or COOX, where X isC₁-C₄-alkyl,

(b) one of the substituents R⁵ or R⁶ is —COONY₂ and the othersubstituent is CONH₂, where Y is C₁-C₄-alkyl or hydrogen,

(c) R⁵ and R⁶ are together —CO—O—CO—.

Particular preference is given to those derivatives of phthalic acidwhere R¹, R², R³ and R⁴ are each hydrogen, and among these especially tothe di-(C₁-C₃-alkyl) phthalates, in particular to dimethyl phthalate.

The electrochemical conversion of these starting materials can beeffected for example by the method described in DE-A 196 18 854.

The electrolyte is customarily a 2-40% strength by weight solution ofphthalic acid or of a phthalic acid derivative in an organic solvent ora mixture of an organic solvent and water, the mixture generallycomprising less than 50% by weight, preferably less than 25% by weight,particularly preferably less than 5% by weight, of water.

Useful organic solvents are in particular aliphatic C₁-C₄-alcohols,especially methanol or ethanol, or mixtures of such alcohols with acarboxamide such as dimethylformamide or tert-butylformamide.

Examples of conducting salts present in the electrolytes are quaternaryammonium salts, such as tetra(C₁-C₄-alkyl)ammonium halides ortetrafluoroborates and preferably methyltributylammonium ormethyltriethylammonium methosulfate, customarily in amounts of from 0.4to 10% by weight, based on the electrolyte.

For the anodic coproduction process it is advisable to use as anodicdepolarizer customary organic compounds whose suitability forelectrochemical oxidation is common knowledge among those skilled in theart. Some anodic coproduction processes are preferably carried out inthe presence of a mediator. Suitable anodic coproduction processes aredescribed for example in D. Kyriakou, Modern Electroorganic Chemistry,Springer, Berlin 1994, chapter 4.2.

Suitable anodic coproduction processes are especially the oxidations ofC—O or C—N single or double bonds, for example the oxidation ofcarboxylic acids, or the oxidative C—C coupling especially ofnapthalenes or activated CH groups and the oxidation of methyl groupsattached to an aromatic nucleus to give aldehydes.

It is particularly advantageous to use methylbenzene or ring-substitutedderivatives of methylbenzene, where from 1 to 3 hydrogen atoms of thephenyl radical can be replaced by C₁-C₆-alkyl radicals or C₁-C₄-alkoxyradicals. Examples of such anodic depolarizers are p-xylene andp-tert-butyltoluene.

When preparing aldehydes as coproducts, it is advisable to use thealcohols mentioned as solvents, since the aldehdyes are acetalized andprotected against further oxidation.

Suitable mediators are in particular halogen compounds, especiallybromides or iodides.

The other process parameters such as temperature and current density arenot crucial, as long as they are kept within the customary framework forelectrochemical conversions of organic compounds. They are moreparticularly specified in DE-A 25 10 920 for example.

When the reaction has proceeded to the stage where the molar ratio (M)of the portion of phthalide to the sum of the proportion of phthalideand phthalic acid or phthalic acid derivatives in the electrolyte iswithin the range from 0.8:1 to 0.99:1, preferably within the range from0.88:1 to 0.95:1, the electrolyte is discharged from the electrolyticcell.

The reaction can be carried out both batchwise and continuously.

If the reaction process is carried out continuously, it is advantageousto adjust the continuous discharge of the electrolyte and the continuoussupplementation of the inert constituents of the electrolyte, as of thesolvents and conducting salts and of the starting materials for theelectrochemical reaction, to each other and to the reaction rate in sucha way that the concentration of all constituents of the electrolyteremains essentially constant. This applies in particular to the molarratio (M) which varies within the range defined.

In general, the discharged electrolyte, i.e., the reaction mixture, isworked up distillatively prior to crystallization, as described above.

The mother liquor formed in the purification process of the inventionand any wash liquor obtained can be recycled into the electrolysis cellwithout further workup, since they consist essentially of a mixture ofphthalide and the corresponding starting compound.

The reaction mixture used for purification can be obtained from thehomogeneously or heterogeneously catalyzed hydrogenation of phthalicacid derivatives.

The composition of the reaction mixture, the underlying reaction and thecatalysts used are described for example in EP-A-0 542 037, EP-A-0 089417, EP-A-0 420 062 and DE-A-32 45 544.

We claim:
 1. The process of recovery for phthalide from an as-obtainablephthalide synthesis reaction mixture by (a) distilling compounds havinga boiling point below the boiling point of said phthalide from saidreaction mixture, provided such compounds are present in said reactionmixtures, to obtain a crude phthalide as bottom product, (b)crystallizing said phthalide from a melt of said crude phthalide withoutuse of other solvents or other assistants.
 2. The process of claim 1,wherein said crystallizing is effected on a cooled surface on which thecrystals grow.
 3. The process of claim 1, wherein said crystallizing iseffected as a suspension crystallization.
 4. The process of claim 1,wherein said crystallizing is effected in multiple stages as afractional crystallization.
 5. The process of claim 1, wherein thecrystals obtained in step (b) are further purified by washing.
 6. Theprocess of claim 1, wherein the crystals obtained in step (b) arefurther purified by sweating by local melting-off of impure regions ofthe crystals.
 7. The process of claim 1, wherein the crystals obtainedin step (b) are further purified by washing and sweating.
 8. The processof claim 1, wherein said reaction mixture is obtained from anelectrolytic reduction.
 9. The process of claim 8, wherein said reactionmixture comprises solvents, conducting salts, anodic depolarizers,mediators or mixtures thereof.
 10. The process of claim 1, wherein saidreaction mixture is obtained from a homogeneously catalyzedhydrogenation of phthalic acid derivatives in the presence of a catalystcomprising ruthenium and an organic phosphine.
 11. The process of claim1, wherein in said reaction mixture is obtained from a heterogeneouslycatalyzed hydrogenation of phthalic acid derivative in the presence of ahydrogenation catalyst, which is essentially free from Lewis acids or anickel catalyst of low nickel content.
 12. A process for recoveringphthalide from an as-obtained phthalide synthesis reaction mixture by(a) distilling compounds having a boiling point below the boiling pointof said phthalide from said reaction mixture, provided such compoundsare present in said reaction mixtures, to obtain a crude phthalide asbottom product, (b) crystallizing said phthalide from a melt of saidcrude phthalide without use of other solvents or other assistantswherein said crystallizing is effected on a cooled surface on which thecrystals grow.
 13. The process of recovery for phthalide from anas-obtainable phthalide synthesis reaction mixture by (a) distillingcompounds having a boiling point below the boiling point of saidphthalide from said reaction mixture, provided such compounds arepresent in said reaction mixtures, to obtain a crude phthalide as bottomproduct, (b) crystallizing said phthalide from a melt of said crudephthalide without use of other solvents or other assistants, whereinsaid crystallizing is effected as a suspension crystallization, whereinthe heat removed is effected by cooling in a heat transferor.
 14. Theprocess of claim 6, wherein the sweating is carried out on belt filters.